Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be highly metastatic, with most patients who succumb to this disease dying of complications caused by their metastatic disease burden. Most preclinical studies of metastasis, however, study the dissemination and colonization of metastasis, and have failed to focus on the treatment of established metastases. The overall goal of our proposed studies, therefore, is to utilize preclinical Genetically Engineered (GEM) and Patient Derived Xenografts (PDX) models of TNBC to determine the efficacy of standard-of-care chemotherapy regimens for the treatment of established metastatic disease. Specifically, these studies will uniquely compare the therapeutic response of TNBCs in their orthotopic site versus the response of established lung metastases, both in immunocompromised models and those with an intact immune system. Recent technological advances using lentiviral vectors allow the efficient introduction of fluorescent and bioluminescent markers into primary tumors to facilitate both non-invasive imaging of metastases as well as re-isolation of transduced cells following treatment for detailed genomic analyses. The proposed therapeutic regimens have been chosen based upon their known efficacy for the treatment of primary TNBC disease in humans. In addition we will also examine the frequency and biology of Tumor Initiating Cells within these TNBC models, and determine if and how these TIC properties change according to microenvironment, and according to treatment. Because metastases are culpable for >90% of cancer-associated mortality, truly efficacious anti-metastatic therapies are desperately needed and our preclinical studies, therefore, should provide a new paradigm for testing these therapies.